The Present invention relates generally to biocompatible materials, and more particularly to antithrombogenic and antibiotic compositions for use as coatings for artificial prostheses and implants which remain in contact with blood or other physiological fluids.
Garlic (Allium sativum) has been employed as a folk medicine for thousands of years for the prevention of stroke, coronary thrombosis, and atherosclerosis, as well as for treatment of various diseases including infections and vascular disorders. Garlic extracts have also been reputed to reduce serum cholesterol levels and to increase blood coagulation time. More recently, some components of garlic have been shown to have antibiotic properties, while others are potent inhibitors of platelet aggregation, one of the first steps in blood clot formation or thrombosis.
The need for improving the biocompatibility of synthetic materials intended for medical uses is considerable. One approach has been to increase the hydrophilicity of polymer surfaces by chemically grafting water swellable polymers. The known antithrombotic action of specific compounds has been utilized in attempts to prepare nonthrombogenic surfaces either by chemically binding such materials to surfaces, or by physically incorporating them into bulk polymers.
The grafting of polymeric materials to one another is well understood (See, e.g., "Grafting and Attachment of Anti-platelet Agents to poly(Ether-Urethanes)" by C. H. Bamford, I. P. Middleton, and Y. Satake, Bioch. Biophys. Acta 886. 109 (1986).), so that any molecule into which a polymerizable double bond may be introduced may, in principle, be attached to a polymer chosen as the material of fabrication for a prosthesis or implant. An alternative is to copolymerize a molecule already possessing a polymerizable olefinic bond (and having desirable antithrombogenic properties) with the prosthesis or implant fabrication polymer, and to graft the resulting material to this fabrication polymer. It is important that the antithrombogenic compound have antibacterial and antifungal (antibiotic) activity as well, since infection is a significant risk in any implant surgery. Past efforts in the production of blood compatible polymers have also included the incorporation of anticoagulants into polymeric matrices for controlled release of the active component. Controlled release methods depend upon diffusion and/or hydrolysis of the active component from the polymeric matrix for the nonthrombogenic effect.
N-vinyl pyrrolidone is a well-known monomeric precursor to poly(N-vinyl pyrrolidone), a water soluble polymer. Copolymerization of this material with sodium vinyl sulfonate and with vinyl sulfuric acid have been reported by J, Bourdais in "Chimie Macromoleculaire. -Copolymerisation du vinylsufonate de sodium. " Comptes Rendus 246, 2374 (1958), and in "Macromolecules. -Copolymeres de N-vinylpyrrolidone et de sulfate acide de vinyle." Comptes Rendus 251, 1636 (1960) by the same author, respectively. That is, successful attempts to synthesize polymeric analogs of heparin, a naturally occurring anticoagulant containing sulfonate groups have been reported, but biological activity of the resulting compounds were not addressed.
More recently others have reported the covalent attachment of a prostaglandin analog (BW 245) to poly(ether-urethanes), poly(ethylene glycol), dextran, and poly(N-vinyl pyrrolidone). The BW 245 was incorporated in side-chains in the polymers by copolymerization of appropriate methacrylate esters of BW 245, and attached in terminal positions of vinyl polymers using haloesters thereof. Such polymers were shown to be effective inhibitors of platelet aggregation in platelet rich plasma using adenosine diphosphate (ADP) induced aggregation.
Detailed accounts of antithrombotic organosulfur compounds found in garlic extracts mention the discovery of a number of platelet aggregation inhibitors (See, e.g., R. Apitz-Castro, S. Cabrera, M. R. Cruz, E. Ledezma, and M. K. Jain, "Effects of Garlic Extract and of Three pure Components Isolated from it on Human platelet Aggregation, Arachidonate Metabolism, Release Reaction and platelet Ultrastructure," Thrombosis Research 32, 155 (1983) and E. Block, S. Ahmad, J. L. Catalfamo, M. K. Jain, and R. Apitz-Castro, "Antithrombotic Organosulfur Compounds from Garlic: Structural, Mechanistic, and Synthetic Studies," J. Am. Chem. Soc. 108, 7045 (1986). The compounds investigated were found generally to exhibit antibacterial and antifungal properties as well. Of these, 2-vinyl-4H-1,3-dithiin was reported to have only moderate activity. Synthetic methods are also available for the production of this dithiin monomer, the simplest involving the vacuum thermolysis of diallyl sulfide to produce dimers of thioacrolein, one of which is the dithiin compound (See, e.g., H. Bock, S. Mohmand, T. Hirabayashi, and A. Semkow, "Thioacrolein," J. Am. Chem. Soc. 104, 312 (1982). To date, homopolymerization or copolymerization of this vinyl organosulfur compound with other vinyl monomers has not been reported. Moreover, it was unknown if the biological activity of this species would be destroyed during the polymerization process. Additionally, such compounds often cannot be polymerized, since the presence of sulfur atoms assists in inhibition of polymerization.
Accordingly, an object of the present invention is to provide a biocompatible composition of matter having antithrombogenic and antibiotic properties for use in biomedical applications where polymeric surfaces are in direct contact with blood or physiological fluids.
Another object of my invention is to prepare a copolymer having antithrombogenic and antibiotic properties for use in biomedical applications where polymeric surfaces are in direct contact with blood or physiological fluids.
Yet another object of my invention is to provide a biocompatible composition of matter that may be used as a surface modification material for preformed polymeric articles such as artificial prostheses and implants in contact with blood or physiological fluids such that the resulting prostheses and implants have antithrombogenic and antibiotic properties.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.